Glycogen dysregulation is a hallmark of aging, and aberrant glycogen drives metabolic reprogramming and pathogenesis in multiple diseases. However, glycogen heterogeneity in healthy and diseased tissues remains largely unknown. Herein, we describe a method to define spatial glycogen architecture in mouse and human tissues using matrix-assisted laser desorption/ionization mass spectrometry imaging. This assay provides robust and sensitive spatial glycogen quantification and architecture characterization in the brain, liver, kidney, testis, lung, bladder, and even the bone. Armed with this tool, we interrogated glycogen spatial distribution and architecture in different types of human cancers. We demonstrate that glycogen stores and architecture are heterogeneous among diseases. Additionally, we observe unique hyperphosphorylated glycogen accumulation in Ewing sarcoma, a pediatric bone cancer. Using preclinical models, we correct glycogen hyperphosphorylation in Ewing sarcoma through genetic and pharmacological interventions that ablate in vivo tumor growth, demonstrating the clinical therapeutic potential of targeting glycogen in Ewing sarcoma.
|Journal||EMBO Molecular Medicine|
|State||Published - Nov 8 2022|
Bibliographical noteFunding Information:
We would like to thank Mrs. Dana Napier for performing histological staining on tissue slices, and the Markey Cancer Center. This study was supported by the National Institute of Health (NIH) grants R35 NS116824 (MSG), P01 NS097197 (MSG), NIH grant R01 AG066653 (RCS), NIH grant R01 R01CA266004 (RCS), NIH/NCI F99CA264165 (LEAY), NIH/NCI training grant T32CA165990 (LRC), St Baldrick's Career Development Award (RCS), V‐Scholar Grant (RCS), Rally Foundation Independent Investigator Grant to (RCS), and Cure Alzheimer's Fund (RCS). This research was also supported by funding from the University of Kentucky Markey Cancer Center and the NIH‐funded Biospecimen Procurement & Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center P30CA177558.
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
- Ewing sarcoma
- MALDI imaging
- glycogen storage disease
- spatial metabolism
ASJC Scopus subject areas
- Molecular Medicine